A damaged nucleus has long been regarded simply as a``bag of broken chromosomes,'' with the DNA free ends moving around and forming connections with randomly encountered partners. Recent evidence shows this picture to be fundamentally wrong. Chromosomes occupy speci®c nuclear domains within which only limited movement is possible. In a human diploid nucleus, 6.6 Â 10 9 base pairs (bp) of DNA are compartmentalized into chromosomes in a way that allows stringent control of replication, differential gene expression, recombination and repair. Most of the chromatin is further organized into looped domains by the dynamic binding of tethered bases to a network of intranuclear proteins, the so-called nuclear scaffold or matrix. Thus, DNA movement is severely curtailed, which limits the number of sites where interchanges can occur. This intricate organizational arrangement may render the genome vulnerable to processes that interfere with DNA repair. Both lower and higher eukaryotic cells perform homologous recombination (HR) and illegitimate recombination (IR) as part of their survival strategies. The repair processes comprising IR must be understood in the context of DNA structural organization, which is fundamentally different in prokaryotic and eukaryotic genomes. In this paper we ®rst review important cellular processes including recombination, DNA repair, and apoptosis, and describe the central elements involved. Then we review the different DNA targets of recombination, and present recent evidence implicating the nuclear matrix in processes which can induce either repair, translocation, deletion, or apoptosis.
Background: Podoplanin-Fc inhibits lymphangiogenesis, but also causes a bleeding disorder by binding to CLEC-2 expressed on platelets. Results: Mutation of threonine 34 in mouse Pdpn-Fc reduces 30-fold the binding to CLEC-2 and does not hamper its antilymphangiogenic activity. Conclusion: PdpnT34A-Fc is an active lymphangiogenesis inhibitor with a better tolerability. Significance: Mutagenesis of Pdpn-Fc is a valid approach to improve this tool for anti-lymphangiogenic therapy.
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